| Title: |
Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors |
| Authors: |
George, J; Walter, V; Peifer, M; Alexandrov, LB; Seidel, D; Leenders, F; Maas, L; Müller, C; Dahmen, I; Delhomme, TM; Ardin, M; Leblay, N; Byrnes, G; Sun, R; De Reynies, A; McLeer-Florin, A; Bosco, G; Malchers, F; Menon, R; Altmüller, J; Becker, C; Nürnberg, P; Achter, V; Lang, U; Schneider, PM; Bogus, M; Soloway, MG; Wilkerson, MD; Cun, Y; McKay, JD; Moro-Sibilot, D; Brambilla, CG; Lantuejoul, S; Lemaitre, N; Soltermann, A; Weder, W; Tischler, V; Brustugun, OT; Lund-Iversen, M; Helland, Å; Solberg, S; Ansén, S; Wright, G; Solomon, B; Roz, L; Pastorino, U; Petersen, I; Clement, JH; Sänger, J; Wolf, J; Vingron, M; Zander, T; Perner, S; Travis, WD; Haas, SA; Olivier, M; Foll, M; Büttner, R; Hayes, DN; Brambilla, E; Fernandez-Cuesta, L; Thomas, RK |
| Publisher Information: |
NATURE PORTFOLIO |
| Publication Year: |
2018 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
https://hdl.handle.net/11343/213150 |
| Availability: |
https://hdl.handle.net/11343/213150 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; CC BY |
| Accession Number: |
edsbas.3D001F65 |
| Database: |
BASE |